Glutathione S-Transferase Alpha 4 Promotes Proliferation and Chemoresistance in Colorectal Cancer Cells

Frontiers in Oncology

Haibo Li¹  Xiaoyun Bian²  Lin Huang²  Jane Y. Wang³  Xiaoyan Ren⁴  Zhanhu Zhang⁵  Lili Xu⁵  Tianqi Li⁵  Xingmin Wang⁵  Chunhua Ma⁵ 

[1] Department of Clinical Laboratory, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, China;Department of Gastroenterology, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, China;Department of Internal Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States;Department of Pathology, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, China;Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, China;

关键词: glutathione S-transferase alpha 4;    colorectal cancer;    proliferation;    reactive oxygen species;    chemoresistance;   

DOI  :  10.3389/fonc.2022.887127

来源: DOAJ

【 摘 要 】

Glutathione S-transferase alpha 4 (GSTA4) is a phase II detoxifying enzyme that is overexpressed in colorectal cancer (CRC) and regulated by the oncogenic transcription factor AP-1. However, the role of GSTA4 in these CRC cells remains unclear. In this study, we investigated the roles of GSTA4 in the CRC cells by inactivating GSTA4 in HCT116 human CRC cells (Defined as HCT116ΔGSTA4) using the CRISPR/Cas9 gene editing. Cell proliferation, clonogenicity, and susceptibility to chemotherapeutic drugs were analyzed in vitro and in a xenograft model. The results showed that loss of GSTA4 significantly decreased cell proliferation and clonogenicity, whereas it increased intracellular reactive oxygen species and cell susceptibility to 5-fluorouracil (5-FU) and oxaliplatin. Additionally, exposure of HCT116ΔGSTA4 cells to 5-FU increased the expression of γH2AX, a hallmark of double-stranded DNA breaks. In contrast, no remarkably increased γH2AX was noted in oxaliplatin-treated HCT116ΔGSTA4 cells compared with HCT116 cells. Moreover, loss of GSTA4 blocked the AKT and p38 MAPK pathways, leading to proliferative suppression. Finally, the xenograft model showed decreased tumor size for HCT116ΔGSTA4 cells compared with HCT116 cells, confirming in vitro findings. These findings suggest that GSTA4 is capable of promoting proliferation, tumorigenesis, and chemoresistance and is a potential target for CRC therapy.

【 授权许可】

Unknown